Flavone Acetic Acid (FAA) augments natural killer (NK) cell activity in both humans and rodents after in vivo administration and synergizes with interleukin-2 for treatment of murine renal cancer. Flavones as a class of natural compounds can have multiple biological effects when utilized in cancer therapy. The aim of this investigation is to define the biochemical pathways and molecular mechanisms by which flavone exhibits its species specificity, in order to develop a model a similar class of drugs whch would be active on human cells. Our studies utilizing the mouse macrophage cell line Ana-1 have indicated that in addition to the induction of cytokine mRNA by FAA, activation of DNA binding proteins occurs as a result of FAA treatment. We have found that NFkappaB proteins and STAT proteins are induced within 3 hours following FAA treatment. While it appears the NFkappaB activation may be direct, STAT protein activation may be indirect as treatment with cycloheximide blocks the appearance of nuclear STAT proteins. We also have analyzed the FAA analog, DMXX, and found that this drug, but not FAA, was capable of inducing IL-8 mRNA in human PBMC. Interestingly, this drug did not induce IL-8 in all donors, indicating that there is extensive donor variability in the response. This is an important finding, given the fact that DMXX is being tested in clinical trials in New Zealand and England. In addition, DMXX did not induce NFkappaB activation when tested on the human cell line HL60. Our increased understanding of how agents such as FAA and DMXX effect cytokine gene expression would permit us to identify the biochemical events involved in this process and lead to the eventual development of drug analogs which may prove effective in clinical trials.